Important role in the regeneration of neurons disrupted
This study of Atlastin (associated with SPG3A HSP when impaired) production in cancer cells of the rat kidney found that a particular pathway for calcium metabolism likely plays an important role in the regeneration of neurons. When Atlastin is impaired through mutations in the SPG3A gene and causes HSP, it is likely partly because it undermines this particular calcium metabolism pathway.
Homotypic membrane fusion of the endoplasmic reticulum (ER) is mediated by a class of dynamin-like GTPases known as atlastin (ATL). Depletion of or mutations in ATL cause an unbranched ER morphology and hereditary spastic paraplegia (HSP), a neurodegenerative disease characterized by axon shortening in corticospinal motor neurons and progressive spasticity of the lower limbs.
How ER shaping is linked to neuronal defects is poorly understood. Here, we show that dominant-negative mutants of ATL1 in PC-12 cells inhibit nerve growth factor (NGF)-induced neurite outgrowth. Overexpression of wild-type or mutant ATL1 or depletion of ATLs alters ER morphology and affects store-operated calcium entry (SOCE) by decreasing STIM1 puncta formation near the plasma membrane upon calcium depletion of the ER. In addition, blockage of the STIM1-Orai pathway effectively abolishes neurite outgrowth of PC-12 cells stimulated by NGF.
These results suggest that SOCE plays an important role in neuronal regeneration, and mutations in ATL1 may cause HSP, partly by undermining SOCE.
SOURCE: Sci Rep. 2017 Feb 27;7:43490. doi: 10.1038/srep43490. PMID: 28240257
Atlastin regulates store-operated calcium entry for nerve growth factor-induced neurite outgrowth.
Li J1, Yan B2, Si H3, Peng X3, Zhang SL3, Hu J2.
1 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, and Tianjin Key Laboratory of Protein Sciences, Tianjin 300071, China.
2 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
3 Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, Texas, USA.